Accession Number : AD1041789


Title :   Molecular Determinants of Hormone Refractory Prostate Cancer


Descriptive Note : Technical Report,01 Jul 2012,30 Jun 2017


Corporate Author : Dana-Farber Cancer Institute Boston United States


Personal Author(s) : Choudhury, Atish


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1041789.pdf


Report Date : 01 Jul 2017


Pagination or Media Count : 44


Abstract : We have performed a high throughput, in vivo genetic screen to identify kinases that permit androgen-dependent transformed prostate epithelial cells (LHSR-AR cells) to form tumors in female animals. In addition to known prostate cancer oncogenes and mediators of androgen independence (mutated KRAS, constitutively active MEK, RAF1, ERBB2, AKT1, PIM1 and PIM2), overexpression of the Never In Mitosis A (NIMA) related kinase 6 (NEK6) reproducibly yielded androgen-independent tumors. NEK6 is overexpressed in prostate cancer cell lines compared to their normal counterparts and is overexpressed in a subset of human prostate cancers. Expression of NEK6confers castration resistance to established tumors in male mice, and suppressing NEK6 expression restores sensitivity to castration. Castration-resistant tumors generated through NEK6 overexpression are predominantly squamous in histology and AR negative. Phosphoproteome analysis reveals the transcription factor FOXJ2 to be a novel substrate. The gene expression profile mediated by NEK6overexpression in tumors from castrated mice demonstrates elements of both differentiation and immune signaling, and a phosphomimetic form of FOXJ2 leads to transcriptions of newly identified NEK6 transcriptional targets. These studies reveal a novel mechanism of resistance in androgen pathway independent prostate cancer (APIPC). Analysis of a genome-wide ORF screen for genes conferring androgen-independent proliferation of LNCaP cells in vitro suggests CREB5 as a novel mediator of castration resistance.


Descriptors :   prostate cancer , resistance(biology) , epithelial cells , neoplasms , genetic markers , gene expression , cell line


Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology


Distribution Statement : APPROVED FOR PUBLIC RELEASE